RNA editing is a post-transcriptional processing mechanism that results in an RNA sequence that is different from that encoded by the genomic DNA and thereby diversifies the gene product and function. The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine residues into inosine (A-to-I editing) in double-stranded RNA (dsRNA) through the action of double-stranded RNA-specific adenosine deaminases, or ADAR, enzymes.
ADAR is an enzyme that in humans is encoded by the ADAR gene (ADAR1 is an acronym for “adenosine deaminase acting on RNA 1”). ADAR1 RNA edits by site-specific deamination of adenosines. The ADAR1 enzyme destabilizes double stranded RNA through conversion of adenosine to inosine. The ADAR1 enzyme modifies cellular and viral RNAs, including coding and noncoding RNAs. ADAR1 is an RNA editing enzyme, required for hematopoiesis. ADAR1+/− chimeric embryos die before embryonic day 14 with defects in the hematopoietic system. Regulated levels of ADAR1 expression are critical for embryonic erythropoiesis in the liver. Mutations in the ADAR gene have been associated with dyschromatosis symmetrica hereditaria. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
Traditional CML treatment, such as hydroxyurea and imatinib, is a great financial burden on patients. Moreover, they are not efficient at eradicate leukemia cancer stem cells, which often leads to disease progression and relapse. New drugs that target at cancer stem cells are urgently needed for patient care.
Studies suggested that leukemia stem cells (LSC) promote therapeutic resistance, relapse and disease progression, the leading causes of leukemia mortality, as a result of enhanced survival and self-renewal combined with a propensity to become dormant in supportive microenvironments. Therapies capable of breaking LSC quiescence while sparing normal hematopoietic stem cell (HSC) function have remained elusive. In chronic myeloid leukemia (CML) mouse models, Sonic hedgehog (Shh) pathway activation promotes LSC maintenance. However, the comparative role of Shh signaling in human normal HSC and LSC quiescence induction and self-renewal had not been determined.
Signal transducer and activator of transcription 5A (STAT5a) is a protein that in humans is encoded by the STAT5A gene. The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated by, and mediates the responses of many cell ligands, such as IL2, IL3, IL7 GM-CSF, erythropoietin, thrombopoietin, and different growth hormones. Activation of this protein in myeloma and lymphoma associated with a TEL/JAK2 gene fusion is independent of cell stimulus and has been shown to be essential for the tumorigenesis.
Janus kinase 2 (JAK2) is a human protein that has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family, and the gp130 receptor family (e.g., IL-6R), and the single chain receptors such as Epo-R. JAK2 gene fusions with the TEL(ETV6) and PCMI genes have been found in leukemia patients. Mutations in JAK2 have been implicated in myeloproliferative disorders.